Keytruda

Keytruda Mechanism of Action

pembrolizumab

Manufacturer:

Merck Sharp & Dohme

Distributor:

Merck Sharp & Dohme
Full Prescribing Info
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Pharmacotherapeutic group: Pembrolizumab (KEYTRUDA) is an antineoplastic agent, monoclonal antibody.
Pharmacology: Pharmacodynamics: Mechanism of Action: PD-1 is an immune-checkpoint receptor that limits the activity of T lymphocytes in peripheral tissues. The PD-1 pathway is an immune control checkpoint that may be engaged by tumor cells to inhibit active T-cell immune surveillance. Pembrolizumab (KEYTRUDA) is a high affinity antibody against PD-1, which exerts dual ligand blockade of the PD-1 pathway, including PD-L1 and PD-L2, on antigen presenting or tumor cells. By inhibiting the PD-1 receptor from binding to its ligands, Pembrolizumab (KEYTRUDA) reactivates tumor-specific cytotoxic T lymphocytes in the tumor microenvironment and reactivates anti-tumor immunity.
In peripheral blood of patients who received Pembrolizumab (KEYTRUDA) 2 mg/kg every 3 weeks or 10 mg/kg every 2 weeks or 3 weeks, an increased percentage of activated (i.e., HLA-DR+) CD4+ and CD8+ T-cells was observed after treatment at all doses and schedules without an increase in the circulating T-lymphocyte number.
Clinical Studies: Clinical efficacy and safety: Melanoma: KEYNOTE-006: Controlled trial in melanoma patients naive to treatment with ipilimumab: The safety and efficacy of Pembrolizumab (KEYTRUDA) were investigated in KEYNOTE-006, a multicenter, controlled, Phase III study for the treatment of unresectable or metastatic melanoma in patients who were naive to ipilimumab and who received no or one prior systemic therapy. Patients were randomized (1:1:1) to receive Pembrolizumab (KEYTRUDA) at a dose of 10 mg/kg every 2 (n=279) or 3 weeks (n=277) or ipilimumab (n=278). Randomization was stratified by line of therapy, ECOG performance status, and PD-L1 expression status. The study excluded patients with autoimmune disease or those receiving immunosuppression; previous severe hypersensitivity to other monoclonal antibodies; and HIV, hepatitis B or hepatitis C infection. Patients with BRAF V600E mutant melanoma were not required to have received prior BRAF inhibitor therapy.
Patients were treated with Pembrolizumab (KEYTRUDA) until disease progression or unacceptable toxicity. Clinically stable patients with initial evidence of disease progression were permitted to remain on treatment until disease progression was confirmed. Assessment of tumor status was performed at 12 weeks, then every 6 weeks through week 48, followed by every 12 weeks thereafter.
Of the 834 patients in KEYNOTE-006, 60% were male, 44% were ≥65 years (median age was 62 years [range 18-89]) and 98% were white. Sixty-six percent had no prior systemic therapies and thus received study therapy as first-line treatment whereas 34% had one prior therapy and thus received study therapy as second-line treatment. Thirty-one percent had an ECOG PS of 1 and 69% had an ECOG PS of 0. Eighty percent of patients were PD-L1 positive (PD-L1 membrane expression in ≥1% of cells within tumor nests as assessed prospectively by an immunohistochemistry research assay with the 22C3 anti-PD-L1 antibody) and 18% were PD-L1 negative. Sixty-five percent of patients had M1c stage, 32% had elevated LDH and 9% had brain metastases. BRAF mutations were reported in 302 (36%) patients. Among patients with BRAF mutant tumors, 139 (46%) were previously treated with a BRAF inhibitor. Baseline characteristics were well-balanced across treatment arms.
The primary efficacy outcome measures were overall survival (OS) and progression free survival (PFS; as assessed by Integrated Radiology and Oncology Assessment [IRO] review using Response Evaluation Criteria in Solid Tumors [RECIST 1.1]). Secondary efficacy outcome measures were overall response rate (ORR) and response duration. Table 1 summarizes key efficacy measures. (See Table 1.)

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The final analysis was performed after all patients had at least 21 months of follow-up. The final OS analysis was performed after 383 patient events [119 for Pembrolizumab (KEYTRUDA) 10 mg/kg every 3 weeks, 122 for Pembrolizumab (KEYTRUDA) 10 mg/kg every 2 weeks and 142 for ipilimumab]. The OS HRs vs. ipilimumab were 0.68 (95% CI: 0.53, 0.86; p<0.001) for patients treated with Pembrolizumab (KEYTRUDA) 10 mg/kg every 3 weeks and 0.68 (95% CI: 0.53, 0.87; p<0.001) for patients treated with Pembrolizumab (KEYTRUDA) 10 mg/kg every 2 weeks. The OS rate at 18 months and 24 months were 62% and 55% respectively for Pembrolizumab (KEYTRUDA) 10 mg/kg every 3 weeks, 60% and 55% respectively for Pembrolizumab (KEYTRUDA) 10 mg/kg every 2 weeks, and 47% and 43% respectively for ipilimumab. At the final analysis, a long-term PFS analysis was performed based on 566 patient events [183 for Pembrolizumab (KEYTRUDA) 10 mg/kg every 3 weeks, 181 for Pembrolizumab (KEYTRUDA) 10 mg/kg every 2 weeks and 202 for ipilimumab]. The PFS HRs vs. ipilimumab were 0.61 (95% CI: 0.50, 0.75) for patients treated with Pembrolizumab (KEYTRUDA) 10 mg/kg every 3 weeks and 0.61 (95% CI: 0.50, 0.75) for patients treated with Pembrolizumab (KEYTRUDA) 10 mg/kg every 2 weeks. (See Figures 1 and 2). The percentage of responders with an ongoing response at 18 months was 68% for Pembrolizumab (KEYTRUDA) 10 mg/kg every 3 weeks, 71% for Pembrolizumab (KEYTRUDA) 10 mg/kg every 2 weeks and 70% for ipilimumab. (See Figures 1 and 2.)

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Sub-population analysis by BRAF mutation status: A subgroup analysis was performed as part of the final analysis of KEYNOTE-006 in patients who were BRAF wild type, BRAF mutant without prior BRAF treatment and BRAF mutant with prior BRAF treatment. The PFS hazard ratios (HRs) {pooled Pembrolizumab (KEYTRUDA) [10 mg/kg every 2 or 3 weeks] vs. ipilimumab} were 0.61 (95% CI: 0.49, 0.76) for BRAF wild type, 0.52 (95% CI: 0.35, 0.78) for BRAF mutant without prior BRAF treatment, and 0.76 (95% CI: 0.51, 1.14) for BRAF mutant with prior BRAF treatment. The OS HRs for pooled Pembrolizumab (KEYTRUDA) vs. ipilimumab were 0.68 (95% CI: 0.52, 0.88) for BRAF wild type, 0.70 (95% CI: 0.40, 1.22) for BRAF mutant without prior BRAF treatment, and 0.66 (95% CI: 0.41, 1.04) for BRAF mutant with prior BRAF treatment. ORR for pooled Pembrolizumab (KEYTRUDA) vs. ipilimumab was 38% vs. 14% for BRAF wild type, 41% vs. 15% for BRAF mutant without prior BRAF treatment, and 24% vs. 10% for BRAF mutant with prior BRAF treatment.
Sub-population analysis by PD-L1 status: A subgroup analysis was performed as part of the final analysis of KEYNOTE-006 in patients who were PD-L1 positive vs. PD-L1 negative. The PFS HRs {pooled Pembrolizumab (KEYTRUDA) [10 mg/kg every 2 or 3 weeks] vs. ipilimumab} were 0.53 (95% CI: 0.44, 0.65) for PD-L1 positive patients and 0.87 (95% CI: 0.58, 1.30) for PD-L1 negative patients. The OS HRs for pooled Pembrolizumab (KEYTRUDA) vs. ipilimumab were 0.63 (95% CI: 0.50, 0.80) for PD-L1 positive patients and 0.76 (95% CI: 0.48, 1.19) for PD-L1 negative patients.
KEYNOTE-002: Controlled trial in melanoma patients previously-treated with ipilimumab: The safety and efficacy of Pembrolizumab (KEYTRUDA) were investigated in KEYNOTE-002, a multicenter, controlled study for the treatment of unresectable or metastatic melanoma in patients previously treated with ipilimumab and if BRAF V600 mutation-positive, a BRAF or MEK inhibitor. Patients were randomized (1:1:1) to receive Pembrolizumab (KEYTRUDA) at a dose of 2 (n=180) or 10 mg/kg (n=181) every 3 weeks or chemotherapy (n=179; including dacarbazine, temozolomide, carboplatin, paclitaxel, or carboplatin+paclitaxel). The study excluded patients with autoimmune disease or those receiving immunosuppression; a history of severe or life-threatening immune-mediated adverse reactions from treatment with ipilimumab, defined as any Grade 4 toxicity or Grade 3 toxicity requiring corticosteroid treatment (greater than 10 mg/day prednisone or equivalent dose) for greater than 12 weeks; previous severe hypersensitivity to other monoclonal antibodies; a history of pneumonitis or interstitial lung disease; HIV, hepatitis B or hepatitis C infection.
Patients were treated with Pembrolizumab (KEYTRUDA) until disease progression or unacceptable toxicity. Clinically stable patients with initial evidence of disease progression were permitted to remain on treatment until disease progression was confirmed. Assessment of tumor status was performed at 12 weeks, then every 6 weeks through Week 48, followed by every 12 weeks thereafter. Patients on chemotherapy who experienced independently-verified progression of disease after the first scheduled disease assessment were able to crossover and receive 2 mg/kg or 10 mg/kg of Pembrolizumab (KEYTRUDA) every 3 weeks in a double-blind fashion.
Of the 540 patients in KEYNOTE-002, 61% were male, 43% were ≥65 years (median age was 62 years [range 15-89]) and 98% were white. Eighty-two percent of patients had M1c stage, 73% had at least two and 32% had three or more prior systemic therapies for advanced melanoma. Forty-five percent had an ECOG PS of 1, 40% had elevated LDH and 23% had a BRAF mutated tumor. Baseline characteristics were well-balanced across treatment arms.
The primary efficacy outcome measures were PFS (as assessed by IRO review using RECIST 1.1) and OS. Secondary efficacy outcome measures were PFS (as assessed by Investigator using RECIST 1.1), ORR and response duration. Table 8 summarizes key efficacy measures in patients previously treated with ipilimumab, and the Kaplan-Meier curve for PFS is shown in Figure 3. There was no statistically significant difference between Pembrolizumab (KEYTRUDA) and chemotherapy in the final OS analysis that was not adjusted for the potentially confounding effects of crossover. Of the patients randomized to the chemotherapy arm, 55% crossed over and subsequently received treatment with Pembrolizumab (KEYTRUDA). (See Table 2.)

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At the final analysis, a long-term PFS analysis was performed based on 466 PFS events (150 for Pembrolizumab (KEYTRUDA) 2 mg/kg every 3 weeks; 144 for Pembrolizumab (KEYTRUDA) 10 mg/kg every 3 weeks and 172 for chemotherapy). The PFS HRs vs. chemotherapy were 0.58 (95% CI: 0.46, 0.73) for patients treated with Pembrolizumab (KEYTRUDA) 2 mg/kg every 3 weeks and 0.47 (95% CI: 0.37, 0.60 for patients treated with Pembrolizumab (KEYTRUDA) 10 mg/kg every 3 weeks (See Figure 3).

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KEYNOTE-001: Open-label study in melanoma patients: The safety and efficacy of Pembrolizumab (KEYTRUDA) were also investigated in an uncontrolled, open-label study for the treatment of unresectable or metastatic melanoma. Efficacy was evaluated for 276 patients from two defined cohorts of KEYNOTE-001, one which included patients previously treated with ipilimumab (and if BRAF V600 mutation-positive, a BRAF or MEK inhibitor) and another which included patients naïve to treatment with ipilimumab. Patients were randomized to receive Pembrolizumab (KEYTRUDA) at a dose of 2 mg/kg every 3 weeks or 10 mg/kg every 3 weeks. Patients were treated with Pembrolizumab (KEYTRUDA) until disease progression or unacceptable toxicity. Clinically stable patients with initial evidence of disease progression were permitted to remain on treatment until disease progression was confirmed. Exclusion criteria were similar to those of KEYNOTE-002.
Of the 89 patients receiving 2 mg/kg of Pembrolizumab (KEYTRUDA) who were previously treated with ipilimumab, 53% were male, 33% were ≥65 years of age and the median age was 59 years (range 18-88). All but two patients were white. Eighty-four percent of patients had M1c stage and 8% had a history of brain metastases. Seventy-eight percent of patients had at least two and 35% had three or more prior systemic therapies for advanced melanoma. BRAF mutations were reported in 13% of the study population.
Of the 51 patients receiving 2 mg/kg of Pembrolizumab (KEYTRUDA) who were naïve to treatment with ipilimumab, 63% were male, 35% were ≥65 years of age and the median age was 60 years (range 35-80). All but one patient was white. Sixty-three percent of patients had M1c stage and 2% had a history of brain metastases. Forty-five percent had no prior therapies for advanced melanoma. BRAF mutations were reported in 39% of the study population.
The primary efficacy outcome measure was ORR as assessed by independent review using confirmed responses and RECIST 1.1. Secondary efficacy outcome measures were disease control rate (DCR; including complete response, partial response and stable disease), response duration, PFS, and OS. Tumor response was assessed at 12-week intervals. Table 3 summarizes key efficacy measures in patients, previously treated or naïve to treatment with ipilimumab, receiving Pembrolizumab (KEYTRUDA) at the recommended dose based on a minimum follow-up time of 30 months for all patients. (See Table 3.)

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Results for patients previously treated with ipilimumab (n=84) and naïve to treatment with ipilimumab (n=52) who received 10 mg/kg of Pembrolizumab (KEYTRUDA) every 3 weeks were similar to those seen in patients who received 2 mg/kg of Pembrolizumab (KEYTRUDA) every 3 weeks.
Non-Small Cell Lung Carcinoma: KEYNOTE-024: Controlled trial of NSCLC patients naïve to treatment: The efficacy of Pembrolizumab (KEYTRUDA) was investigated in KEYNOTE-024, a multicenter, randomized, controlled trial. Key eligibility criteria were metastatic NSCLC, PD-L1 expression TPS of 50% or greater by an immunohistochemistry assay using the PD-L1 IHC 22C3 pharmDx Kit, and no prior systemic treatment for metastatic NSCLC. Patients with EGFR or ALK genomic tumor aberrations; autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Patients were randomized (1:1) to receive Pembrolizumab (KEYTRUDA) 200 mg every 3 weeks (n=154) or investigator's choice platinum-containing chemotherapy (n=151; including pemetrexed+carboplatin, pemetrexed+cisplatin, gemcitabine+cisplatin, gemcitabine+carboplatin, or paclitaxel+carboplatin. Non-squamous patients could receive pemetrexed maintenance). Patients were treated with Pembrolizumab (KEYTRUDA) until unacceptable toxicity or disease progression. Treatment could continue beyond disease progression if the patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Patients without disease progression could be treated for up to 24 months. Treatment with Pembrolizumab (KEYTRUDA) could be reinitiated for subsequent disease progression and administered for up to 1 additional year. Assessment of tumor status was performed every 9 weeks. Patients on chemotherapy who experienced independently-verified progression of disease were able to crossover and receive Pembrolizumab (KEYTRUDA).
Among the 305 patients in KEYNOTE-024, baseline characteristics were: median age 65 years (54% age 65 or older); 61% male; 82% White and 15% Asian; and 35% and 65% with an ECOG performance status 0 and 1, respectively. Disease characteristics were squamous (18%) and non-squamous (82%); M1 (99%); and brain metastases (9%).
The primary efficacy outcome measure was PFS as assessed by blinded independent central review (BICR) using RECIST 1.1. Secondary efficacy outcome measures were OS and ORR (as assessed by BICR using RECIST 1.1). Table 4 summarizes key efficacy measures for the entire ITT population. (See Table 4, Figure 4 and Figure 5.)

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The improved benefit as assessed by PFS, OS, ORR, and response duration for Pembrolizumab (KEYTRUDA) as compared to chemotherapy in the population studied was associated with improvements in health-related quality of life (HRQoL). The change from baseline to Week 15 showed a meaningful improvement in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30 global health status/QoL score for patients receiving Pembrolizumab (KEYTRUDA) compared to chemotherapy (difference in LS means = 7.82; 95% CI: 2.85, 12.79; two-sided p=0.002). The time to deterioration in the EORTC QLQ-LC13 composite endpoint of cough, dyspnea, and chest pain was prolonged for patients receiving Pembrolizumab (KEYTRUDA) compared to chemotherapy (HR=0.66; 95% CI: 0.44, 0.97; two-sided p=0.029), where deterioration is defined as a confirmed 10-point or greater score decrease from baseline in any one of these three symptoms.
KEYNOTE-021: Controlled trial of combination therapy in NSCLC patients naive to treatment: The efficacy of Pembrolizumab (KEYTRUDA) in combination with pemetrexed and carboplatin was investigated in a multicenter, randomized, controlled cohort of KEYNOTE-021. Key eligibility criteria were metastatic non-squamous NSCLC and no prior systemic treatment for metastatic NSCLC.
Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Patients were randomized (1:1) to receive one of the following regimens: Pembrolizumab (KEYTRUDA) 200 mg with pemetrexed 500 mg/m2 and carboplatin AUC 5 mg/mL/min intravenously every 3 weeks for 4 cycles followed by Pembrolizumab (KEYTRUDA) 200 mg intravenously every 3 weeks and optional pemetrexed 500 mg/m2 every 3 weeks; Pemetrexed 500 mg/m2 and carboplatin AUC 5 mg/mL/min intravenously every 3 weeks for 4 cycles followed by optional pemetrexed 500 mg/m2 every 3 weeks.
Patients were treated with Pembrolizumab (KEYTRUDA) until unacceptable toxicity or disease progression. Treatment could continue beyond disease progression if the patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Patients without disease progression could be treated for up to 24 months. Treatment with Pembrolizumab (KEYTRUDA) could be reinitiated for subsequent disease progression and administered for up to 1 additional year.
Assessment of tumor status was performed every 6 weeks through Week 18, followed by every 9 weeks thereafter. Patients on chemotherapy alone who experienced independently-verified progression of disease were offered Pembrolizumab (KEYTRUDA) as monotherapy.
Among the 123 patients in KEYNOTE-021 [60 patients in the Pembrolizumab (KEYTRUDA) combination arm and 63 in the chemotherapy alone arm], baseline characteristics were: median age of 64 years (48% age 65 or older); 39% male; 87% White and 8% Asian; 56% ECOG performance status of 1; 36% with PD-L1 TPS <1%; 3% with advanced localized disease, 97% with metastatic disease; and 12% with history of brain metastases. No patients had sensitizing EGFR or ALK genomic aberrations.
The major efficacy outcome measures were ORR and PFS as assessed by BICR using RECIST 1.1. OS was an additional efficacy outcome measure. Table 5 summarizes key efficacy measures. (See Table 5 and Figure 6.)

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KEYNOTE-010: Controlled trial of NSCLC patients previously treated with chemotherapy: The efficacy of Pembrolizumab (KEYTRUDA) was investigated in KEYNOTE-010, a multicenter, randomized, controlled trial. Key eligibility criteria were advanced NSCLC that had progressed following platinum-containing chemotherapy, and if appropriate, targeted therapy for ALK or EGFR mutations, and PD-L1 expression TPS of 1% or greater by a clinical trial assay version of the PD L1 IHC 22C3 pharmDx™ kit. Patients with autoimmune disease; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Patients were randomized (1:1:1) to receive 2 mg/kg (n=344) or 10 mg/kg (n=346) of Pembrolizumab (KEYTRUDA) every 3 weeks or 75 mg/m2 of docetaxel every 3 weeks (n=343). Patients were treated with Pembrolizumab (KEYTRUDA) until disease progression or unacceptable toxicity. Assessment of tumor status was performed every 9 weeks.
Among the 1033 patients in KEYNOTE-010, baseline characteristics were: median age 63 years (42% age 65 or older); 61% male; 72% White and 21% Asian; and 34% and 66% with an ECOG performance status 0 and 1, respectively. Disease characteristics were squamous (21%) and non-squamous (70%); M1 (91%); brain metastases (15%); and the incidence of genomic aberrations was EGFR (8%) or ALK (1%). Prior therapy included platinum-doublet regimen (100%); patients received one (69%), or two or more (29%) prior therapies.
The primary efficacy outcome measures were OS and PFS as assessed by an independent review committee using RECIST 1.1. Secondary efficacy outcome measures were ORR and response duration. Table 6 summarizes key efficacy measures for the entire ITT population (TPS ≥1%) and for the subgroup of patients with TPS ≥50%. Kaplan-Meier curves for OS (TPS ≥1% and TPS ≥50%) are shown in Figures 7 and 8. (See Table 6, Figure 7 and Figure 8.)

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Efficacy results were similar for the 2 mg/kg and 10 mg/kg Pembrolizumab (KEYTRUDA) arms. Efficacy results for OS were consistent regardless of the age of tumor specimen (new versus archival).
KEYNOTE-001: Open-label study in NSCLC patients previously treated with chemotherapy: The efficacy of Pembrolizumab (KEYTRUDA) was also investigated in a multicenter, open-label, randomized, dose-comparative cohort of KEYNOTE-001. Patients had advanced NSCLC that was PD-L1 positive, with progression of disease following treatment with platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations had disease progression on approved therapy for these aberrations prior to receiving Pembrolizumab (KEYTRUDA). The trial excluded patients with autoimmune disease; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks. Patients were randomized to receive 10 mg/kg of Pembrolizumab (KEYTRUDA) every 2 (n=69) or 3 (n=87) weeks until disease progression or unacceptable toxicity. Assessment of tumor status was performed every 9 weeks. The major efficacy outcome measures were ORR (according to RECIST 1.1 as assessed by blinded independent central review) and duration of response.
The prevalence of patients with a PD-L1 expression TPS greater than or equal to 50% among screened patients with NSCLC as ascertained retrospectively by the companion diagnostic PD-L1 IHC 22C3 pharmDx™ kit was 26%. Among the randomized patients with tumor samples evaluable for PD-L1 expression, 61 had TPS greater than or equal to 50%. The baseline characteristics for this population included: median age 60 years (34% age 65 or older); 61% male; 79% White; and 34% and 64% with an ECOG performance status 0 and 1, respectively. Disease characteristics were squamous and non-squamous (21% and 75%, respectively); M1 (98%); brain metastases (11%); and one (25%), two (31%), or three or more (44%) prior therapies. The mutation status among patients was EGFR (10%), ALK (0%), or Kras (16%).
Efficacy results for NSCLC patients treated with 10 mg/kg every 2 or 3 weeks in KEYNOTE-001 are summarized in Table 7. (See Table 7.)

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Similar ORR results were observed in another group of patients (n=25) with TPS greater than or equal to 50% receiving Pembrolizumab (KEYTRUDA) at a dose of 2 mg/kg every 3 weeks in KEYNOTE-001.
Head and Neck Cancer: KEYNOTE-012: Open-label study in HNSCC patients previously treated with chemotherapy: The efficacy of Pembrolizumab (KEYTRUDA) was investigated in 192 patients with recurrent and/or metastatic HNSCC, regardless of tumor human papilloma virus (HPV) status (33% positive), enrolled in a multicenter, nonrandomized, open-label multi-cohort study (KEYNOTE-012). One cohort (n=132) was included regardless of PD-L1 tumor status. Efficacy is reported for a subgroup of 110 patients with recurrent and/or metastatic HNSCC that progressed on or after treatment with platinum-containing chemotherapy and cetuximab, and for a subgroup of 64 patients with recurrent and/or metastatic HNSCC that progressed on or after treatment with platinum-containing chemotherapy without prior cetuximab. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible.
Patients received Pembrolizumab (KEYTRUDA) 10 mg/kg every 2 weeks (n=53), or 200 mg every 3 weeks (n=121) until disease progression or unacceptable toxicity. Assessment of tumor status was performed every 8 weeks. The major efficacy outcome measures were ORR according to RECIST 1.1, as assessed by blinded independent central review, and duration of response.
Among the 64 patients with disease progression after platinum-containing chemotherapy without prior cetuximab, the baseline characteristics were median age 60 years (28% age 65 or older); 77% male; 75% White, 20% Asian, and 3% Black; 88% had M1 stage disease; and 33% and 67% had an ECOG performance status 0 and 1, respectively. Thirty-six percent of patients had two or more lines of therapy in the recurrent and/or metastatic setting.
Among the 110 patients with disease progression after platinum-containing chemotherapy and cetuximab, the baseline characteristics were median age 60 years (34% age 65 or older); 85% male; 75% White, 14% Asian, and 7% Black; 87% had M1 stage disease; and 27% and 73% had an ECOG performance status 0 and 1, respectively. Eighty percent of patients had two or more lines of therapy in the recurrent and/or metastatic setting.
Efficacy results are summarized in Table 8. (See Table 8.)

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There were objective responses in patients regardless of HPV tumor status.
Classical Hodgkin Lymphoma: KEYNOTE-013 and KEYNOTE-087: Open-label studies in patients with refractory classical Hodgkin Lymphoma, or those who have relapsed after greater than or equal to 3 prior lines of therapy: The efficacy of Pembrolizumab (KEYTRUDA) was investigated in 241 patients with refractory classical Hodgkin Lymphoma, or who have relapsed after 3 or more prior lines of therapy, enrolled in two multicenter, nonrandomized, open-label studies (KEYNOTE-013 and KEYNOTE-087). Both studies included patients regardless of PD-L1 expression. Patients with active, non-infectious pneumonitis, an allogeneic hematopoietic stem cell transplant within the past 5 years (or greater than 5 years but with GVHD), active autoimmune disease or a medical condition that required immunosuppression were ineligible for either trial. Patients received Pembrolizumab (KEYTRUDA) 10 mg/kg every 2 weeks (n=31) or 200 mg every 3 weeks (n=210) until unacceptable toxicity or documented disease progression. Response was assessed using the revised lymphoma criteria by PET CT scans, with the first planned post-baseline assessment at week 12. The major efficacy outcome measures (ORR, CRR, and duration of response) were assessed by blinded independent central review according to the 2007 revised International Working Group (IWG) criteria. Secondary efficacy outcome measures were PFS and OS.
Among KEYNOTE-013 patients, the baseline characteristics were median age 32 years (6% age 65 or older), 58% male, 94% White; and 45% and 55% had an ECOG performance status 0 and 1, respectively. The median number of prior lines of therapy administered for the treatment of cHL was 5 (range 2 to 15). Eighty-seven percent were refractory to at least one prior therapy, including 39% who were refractory to first line therapy. Seventy-four percent of patients had received Auto-SCT, 26% were transplant ineligible; and 42% of patients had prior radiation therapy.
Among KEYNOTE-087 patients, the baseline characteristics were median age 35 years (9% age 65 or older); 54% male; 88% White; and 49% and 51% had an ECOG performance status 0 and 1, respectively. The median number of prior lines of therapy administered for the treatment of cHL was 4 (range 1 to 12). Eighty-one percent were refractory to at least one prior therapy, including 35% who were refractory to first line therapy. Sixty-one percent of patients had received Auto-SCT, 38% were transplant ineligible; 17% had no prior brentuximab vedotin use; and 36% of patients had prior radiation therapy.
Efficacy results are summarized in Table 9. (See Table 9.)

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The improved benefit as assessed by ORR, CRR, and response duration in the KEYNOTE-087 population was accompanied by overall improvements in health-related quality of life (HRQoL) as assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and the European Quality of Life Five Dimensions Questionnaire (EQ-5D). Relative to subjects with stable disease or progressive disease, subjects with a complete or partial response had the largest improvement and the highest proportion with a 10 point or greater increase in their EORTC QLQ-C30 global health status/QoL score, as well as, had the largest improvement in their EQ-5D utility and VAS scores from baseline to Week 12.
Urothelial Carcinoma: KEYNOTE-052: Open label trial in urothelial carcinoma patients ineligible for cisplatin-containing chemotherapy: The efficacy of Pembrolizumab (KEYTRUDA) was investigated in KEYNOTE-052, a multicenter, open-label trial of patients with locally advanced or metastatic urothelial carcinoma who were not eligible for cisplatin-containing chemotherapy. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression.
Patients received Pembrolizumab (KEYTRUDA) 200 mg every 3 weeks until unacceptable toxicity or disease progression. Clinically stable patients with initial evidence of disease progression were permitted to remain on treatment until disease progression was confirmed. Patients without disease progression were treated for up to 24 months. Treatment with pembrolizumab could be reinitiated for subsequent disease progression and administered for up to 1 additional year. Assessment of tumor status was performed at 9 weeks after the first dose, then every 6 weeks through the first year, followed by every 12 weeks thereafter. The major efficacy outcome measures were ORR according to RECIST 1.1 and duration of response. Efficacy is reported for patients who had the opportunity for at least 2 post-baseline scans representing at least 4 months of follow-up.
Among 370 patients with urothelial carcinoma who were not eligible for cisplatin-containing chemotherapy and who had an opportunity for at least 2 post-baseline scans representing at least 4 months of follow-up, baseline characteristics were: median age 74 years (82% age 65 or older); 77% male; and 89% White and 7% Asian. Eighty-seven percent had M1 disease, 13% had M0 disease. Eighty-five percent of patients had visceral metastases, including 21% with liver metastases. Reasons for cisplatin ineligibility included: baseline creatinine clearance of <60 mL/min (50%), ECOG performance status of 2 (32%), ECOG performance status of 2 and baseline creatinine clearance of <60 mL/min (9%), and other (Class III heart failure, Grade 2 or greater peripheral neuropathy, and Grade 2 or greater hearing loss; 9%). Ninety percent of patients were treatment naïve, and 10% received prior adjuvant or neoadjuvant platinum-based chemotherapy. Eighty-one percent had a primary tumor in the lower tract, and 19% of patients had a primary tumor in the upper tract.
The median follow-up time for 370 patients treated with Pembrolizumab (KEYTRUDA) was 9.5 months. Efficacy results are summarized in Table 10. (See Table 10.)

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KEYNOTE-045: Controlled trial in urothelial carcinoma patients previously treated with platinum-containing chemotherapy: The efficacy of Pembrolizumab (KEYTRUDA) was evaluated in KEYNOTE-045, a multicenter, randomized (1:1), active-controlled trial in patients with locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-containing chemotherapy. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression.
Patients were randomized to receive either Pembrolizumab (KEYTRUDA) 200 mg every 3 weeks (n=270) or investigator's choice of any of the following chemotherapy regimens all given intravenously every 3 weeks (n=272): paclitaxel 175 mg/m2 (n=84), docetaxel 75 mg/m2 (n=84), or vinflunine 320 mg/m2 (n=87). Patients received Pembrolizumab (KEYTRUDA) until unacceptable toxicity or disease progression. Clinically stable patients with initial evidence of disease progression were permitted to remain on treatment until disease progression was confirmed. Patients without disease progression were treated for up to 24 months. Treatment with pembrolizumab could be reinitiated for subsequent disease progression and administered for up to 1 additional year. Assessment of tumor status was performed at 9 weeks after randomization, then every 6 weeks through the first year, followed by every 12 weeks thereafter. The major efficacy outcomes were OS and PFS as assessed by BICR per RECIST v1.1. Additional efficacy outcome measures were ORR as assessed by BICR per RECIST v1.1 and duration of response.
Among the 542 randomized patients, the study population characteristics were: median age 66 years (range: 26 to 88), 58% age 65 or older; 74% male; 72% White and 23% Asian; 57% ECOG performance status of 1 or greater; and 96% M1 disease and 4% M0 disease. Eight-seven percent of patients had visceral metastases, including 34% with liver metastases. Eighty-six percent had a primary tumor in the lower tract and 14% had a primary tumor in the upper tract. Fifteen percent of patients had disease progression following prior platinum-containing neoadjuvant or adjuvant chemotherapy as the most recent line of therapy. Twenty-one percent had received 2 or more prior systemic regimens in the metastatic setting. Seventy-six percent of patients received prior cisplatin, 23% had prior carboplatin, and 1% were treated with other platinum-based regimens.
The median follow-up time for 270 patients treated with Pembrolizumab (KEYTRUDA) was 10.3 months. The study demonstrated statistically significant improvements in OS and ORR for patients randomized to Pembrolizumab (KEYTRUDA) as compared to chemotherapy (Table 11 and Figure 9). There was no statistically significant difference between Pembrolizumab (KEYTRUDA) and chemotherapy with respect to PFS. Table 11 and Figure 9 summarize the key efficacy measures. (See Table 11 and Figure 9.)

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Patient-reported outcomes (PROs) were assessed using the EORTC QLQ-C30. A prolonged time to deterioration in the EORTC QLQ-C30 global health status/QoL score was observed for patients treated with pembrolizumab compared to investigator's choice chemotherapy (HR 0.70; 95% CI 0.55- 0.90). Over 15 weeks of follow-up, patients treated with pembrolizumab had stable global health status/QoL scores, while those treated with investigator's choice chemotherapy had a decline in global health status/QoL scores. These results should be interpreted in the context of the open-label study design and therefore taken cautiously.
Gastric Cancer: KEYNOTE-059: Open-label study in gastric cancer patients previously treated with chemotherapy: The efficacy of Pembrolizumab (KEYTRUDA) was investigated in KEYNOTE-059, a multicenter, nonrandomized, open-label multi-cohort trial that enrolled 259 patients with gastric or gastroesophageal junction (GEJ) adenocarcinoma who progressed on at least two prior systemic treatments for advanced disease. Previous treatment must have included a fluoropyrimidine and platinum doublet.
HER2/neu positive patients must have previously received treatment with approved HER2/neu-targeted therapy. Patients with active autoimmune disease or a medical condition that required immunosuppression or with clinical evidence of ascites by physical exam were ineligible.
Patients received Pembrolizumab (KEYTRUDA) 200 mg every 3 weeks until unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at least 4 weeks later with repeat imaging.
Patients without disease progression were treated for up to 24 months. Assessment of tumor status was performed every 6 to 9 weeks. The major efficacy outcome measures were ORR according to RECIST 1.1, as assessed by blinded independent central review, and duration of response.
Among the 259 patients, 57% (n=148) had tumors that expressed PD-L1 with a combined positive score (CPS) of greater than or equal to 1. PD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx Kit. The baseline characteristics of these 148 patients were: median age 64 years (47% age 65 or older); 77% male; 82% White, 12% Asian; and ECOG PS of 0 (43%) and 1 (57%). Eighty-five percent had M1 disease and 7% had M0 disease. Fifty-one percent had two and 49% had three or more prior lines of therapy in the recurrent or metastatic setting.
Efficacy results are summarized in Table 12. (See Table 12.)

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Immunogenicity: In clinical studies in patients treated with pembrolizumab at a dose of 2 mg/kg every three weeks, 200 mg every three weeks, or 10 mg/kg every two or three weeks, 36 (1.8%) of 2034 evaluable patients tested positive for treatment-emergent antibodies against pembrolizumab during treatment with Pembrolizumab (KEYTRUDA) of which 9 (0.4%) patients had neutralizing antibodies against pembrolizumab. There was no evidence of an altered pharmacokinetic or safety profile with anti-pembrolizumab binding or neutralizing antibody development.
Pharmacokinetics: The pharmacokinetics of pembrolizumab was studied in 2993 patients with various cancers who received doses in the range of 1 to 10 mg/kg every 2 weeks, 2 to 10 mg/kg every 3 weeks, or 200 mg every 3 weeks. There are no clinically meaningful differences in pharmacokinetics of pembrolizumab across indications.
Absorption: Pembrolizumab (KEYTRUDA) is dosed via the IV route and therefore is immediately and completely bioavailable.
Distribution: Consistent with a limited extravascular distribution, the volume of distribution of pembrolizumab at steady state is small (6.0 L; coefficient of variation [CV]: 20%). As expected for an antibody, pembrolizumab does not bind to plasma proteins in a specific manner.
Metabolism: Pembrolizumab is catabolized through non-specific pathways; metabolism does not contribute to its clearance.
Elimination: Pembrolizumab clearance (CV%) is approximately 23% lower [geometric mean, 195 mL/day (40%)] after achieving maximal change at steady state compared with the first dose (252 mL/day [CV%: 37%]); this decrease in clearance with time is not considered clinically important. The geometric mean value (CV%) for the terminal half-life (t½) is 22 days (32%).
Steady-state concentrations of pembrolizumab were reached by 16 weeks of repeated dosing with an every 3-week regimen and the systemic accumulation was 2.1-fold. The peak concentration (Cmax), trough concentration (Cmin), and area under the plasma concentration versus time curve at steady state (AUCss) of pembrolizumab increased dose proportionally in the dose range of 2 to 10 mg/kg every 3 weeks.
Special Populations: The effects of various covariates on the pharmacokinetics of pembrolizumab were assessed in population pharmacokinetic analyses. The following factors had no clinically important effect on the clearance of pembrolizumab: age (range 15-94 years), gender, race, mild or moderate renal impairment, mild hepatic impairment, and tumor burden. The relationship between body weight and clearance supports the use of either fixed dose or body weight-based dosing to provide adequate and similar control of exposure.
Renal Impairment: The effect of renal impairment on the clearance of pembrolizumab was evaluated by population pharmacokinetic analysis in patients with mild (GFR <90 and ≥60 mL/min/1.73 m2) or moderate (GFR <60 and ≥30 mL/min/1.73 m2) renal impairment compared to patients with normal (GFR ≥90 mL/min/1.73 m2) renal function. No clinically important differences in the clearance of pembrolizumab were found between patients with mild or moderate renal impairment and patients with normal renal function. Pembrolizumab (KEYTRUDA) has not been studied in patients with severe (GFR <30 and ≥15 mL/min/1.73 m2) renal impairment. (See Dosage & Administration.)
Hepatic Impairment: The effect of hepatic impairment on the clearance of pembrolizumab was evaluated by population pharmacokinetic analysis in patients with mild hepatic impairment [total bilirubin (TB) 1.0 to 1.5 x ULN or AST >ULN as defined using the National Cancer Institute criteria of hepatic dysfunction] compared to patients with normal hepatic function (TB and AST ≤ULN). No clinically important differences in the clearance of pembrolizumab were found between patients with mild hepatic impairment and normal hepatic function. Pembrolizumab (KEYTRUDA) has not been studied in patients with moderate (TB >1.5 to 3 x ULN and any AST) or severe (TB >3 x ULN and any AST) hepatic impairment. (See Dosage & Administration.)
Animal Toxicology: Chronic Toxicity: The safety of pembrolizumab was evaluated in a 1-month and a 6-month repeat-dose toxicity study in Cynomolgus monkeys administered IV doses of 6, 40 or 200 mg/kg once a week in the 1-month study and once every two weeks in the 6-month study, followed by a 4-month treatment-free period. No findings of toxicological significance were observed and the no observed adverse effect level (NOAEL) in both studies was ≥200 mg/kg, which produced exposure multiples of 19 and 94 times the exposure in humans at doses of 10 and 2 mg/kg, respectively. The exposure multiple between the NOAEL and a human dose of 200 mg was 74.
Carcinogenesis: The carcinogenic potential of pembrolizumab has not been evaluated in long-term animal studies.
Mutagenesis: The genotoxic potential of pembrolizumab has not been evaluated.
Reproduction: Animal reproduction studies have not been conducted with Pembrolizumab (KEYTRUDA). The central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining immune tolerance to the fetus. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus and to result in an increase in fetal loss. These results indicate a potential risk that administration of Pembrolizumab (KEYTRUDA) during pregnancy could cause fetal harm, including increased rates of abortion or stillbirth.
Development: Developmental toxicity studies have not been conducted with pembrolizumab. There were no notable effects in the male and female reproductive organs in monkeys based on 1-month and 6-month repeat dose toxicity studies.
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